PI/PD: Jain, Nitya Ph.D. PROJECT SUMMARY The immune system of the newborn faces unique challenges in the period immediately following birth. Thrust from a sterile fetal environment, it is abruptly exposed to an immense array of foreign antigens, the major burden of which is in the form of the microbiota newly colonizing the gastrointestinal tract. Breakdown of tolerance to intestinal microbiota precipitates autoimmunity in adults. Postnatal immunity, however, is largely immature and relies primarily on innate immune effectors for protection against infection and autoimmunity. Both adaptive and innate lymphocytes develop in the thymus. How do the needs of gut immunity get transmitted to the thymus at this critical time in the development of the neonate? It is clear that gut microbiota regulate the maturation of the immune system at mucosal sites. However, a central unresolved question remains how intestinal microbial colonization influences immune cells development in the primary lymphoid organ, the thymus. The long-term goal of this study is to understand how the postnatal immune system develops in the presence of the maturing intestinal microbiota that impacts immunity in adulthood. The specific objective of this proposal is to explore the role of the Toll-like Receptor 2 (TLR2) pathway in mediating entero-thymic communication that regulates the development of immune cell subsets in early life. We propose that TLR2-microbiota interactions shape immune system development in early life. We hypothesize that these interactions impact thymic development of specific immune cell subsets in early life. We will address this in the experiments of the following Specific Aims. Specific Aim 1: Determine in which cell subset is TLR2 required to regulate thymic T cell development. Specific Aim 2: Determine when during ontogeny is TLR2 required to regulate thymic T cell development. Specific Aim 3: Determine the impact of TLR2-deficiency on entero-thymic communication. Microbiota regulation of thymic development is a novel concept and has tremendous therapeutic potential, especially in preterm infants that suffer from severe disorders stemming from immunological imbalances. Strategies targeting microbiota and the host pathways they affect may provide benefits to a substantial number of these preterm infants.